9 research outputs found
Rhodium/Chiral Diene Complexes in the Catalytic Asymmetric Arylation of β‑Pyrazol-1-yl Acrylates
The asymmetric conjugate
addition of arylboronic acids to substituted
and unsubstituted β-pyrazol-1-yl (<i>E</i>)-<i>tert</i>-butyl acrylates <b>4</b> catalyzed by 5 mol %
of the RhÂ(I)/diene <b>2a</b> catalyst provided the corresponding
addition products in 44–98% yield and 91–>99.5% ee.
The method was applied to the formal synthesis of (3<i>S</i>)-3-aryl-3-(pyrazol-1-yl)Âpropanoic acid <b>1b</b> with agonistic
activity toward the human GPR40 G-protein coupled receptor
β‑Selective <i>C</i>‑Arylation of Diisobutylaluminum Hydride Modified 1,6-Anhydroglucose: Synthesis of Canagliflozin without Recourse to Conventional Protecting Groups
The β-selective phenylation
of benzyl and boronate protected
1,6-anhydroglucose and the direct phenylation of unprotected 1,6-anhydroglucose
(<b>10</b>), pretreated with <i>i</i>-Bu<sub>2</sub>AlH, <i>i</i>-Bu<sub>3</sub>Al, Et<sub>3</sub>Al, Me<sub>3</sub>Al, or <i>n</i>-octyl<sub>3</sub>Al, with triphenylalane
or arylÂ(chloro)Âalanes is reported. The utility of the unprotected
version of the method is demonstrated by the synthesis of the SGLT2
inhibitor, canagliflozin (<b>1a</b>), from commercially available <b>10</b> in one C–C bond-forming step. This approach circumvents
the need for conventional protecting groups, and therefore no formal
protection and deprotection steps are required
β‑Selective <i>C</i>‑Arylation of Silyl Protected 1,6-Anhydroglucose with Arylalanes: The Synthesis of SGLT2 Inhibitors
The stereoselective arylation of
hydroxy protected 1,6-anhydro-β-d-glucose with arylalanes
to provide β-<i>C</i>-arylglucosides is reported.
Modification of triarylalanes, Ar<sub>3</sub>Al, with strong Brønsted
acids (HX) or AlCl<sub>3</sub> produced more reactive arylating agents,
Ar<sub>2</sub>AlX, while
the incorporation of alkyl dummy ligands into the arylating agents
was also viable. Me<sub>3</sub>Al and <i>i</i>-Bu<sub>2</sub>AlH were found useful in the <i>in situ</i> blocking of
the C3-hydroxyl group of 2,4-di-<i>O</i>-TBDPS protected
1,6-anhydroglucose. The utility of the method was demonstrated by
the synthesis of the SGLT2 inhibitor, canagliflozin
Rh(I)-Catalyzed 1,4-Conjugate Addition of Alkenylboronic Acids to a Cyclopentenone Useful for the Synthesis of Prostaglandins
An efficient and <i>trans</i>-diastereoselective RhÂ(I)-catalyzed
1,4-conjugate addition reaction of alkenylboronic acids and a homochiral
(<i>R</i>)-4-silyloxycyclopentenone useful for the synthesis
of derivatives of prostaglandins E and F is described for the first
time. The reaction functions under mild conditions and is particularly
rapid (≤6 h) under low power (50 W) microwave irradiation at
30 °C in MeOH in the presence of a catalytic amount of KOH. Under
these conditions, 3 mol % of [RhClÂ(COD)]<sub>2</sub> is typically
required to produce high yields. The method also functions without
microwave irradiation at 3 °C in the presence of a stoichiometric
amount of KOH. Under these conditions, only 1.5 mol % of [RhClÂ(COD)]<sub>2</sub> is needed, but the reaction is considerably slower. The method
accepts a range of aryl- and alkyl-substituted alkenylboronic acids,
and its utility has been demonstrated by the synthesis of PGF<sub>2α</sub> (dinoprost) and tafluprost
Rhodium-Catalyzed Asymmetric Addition of Arylboronic Acids to β‑Nitroolefins: Formal Synthesis of (<i>S</i>)‑SKF 38393
An efficient enantioselective addition of an array of arylboronic
acids to various β-nitrostyrenes catalyzed by a novel and reactive
rhodium–diene catalyst (S/C up to 1000) was developed, providing
β,β-diarylnitroethanes in good to high yields (62–99%)
with excellent enantioselectivities (85–97% ee). The method
was extended to 2-heteroarylnitroolefins and 2-alkylnitroolefins similarly
providing the desired products with high enantioselectivities and
yields. The usefulness of this method was demonstrated in the formal
synthesis of the enantiomer of the dopamine receptor agonist and antagonist,
SKF 38393
Enantioselective and Rapid Rh-Catalyzed Arylation of <i>N</i>‑Tosyl- and <i>N</i>‑Nosylaldimines in Methanol
Enantiomerically
enriched tosyl-protected diarylmethylamines were
rapidly prepared by the asymmetric addition of arylboronic acids to <i>N</i>-tosylaldimines under mild conditions in the presence of
a catalyst prepared in situ from RhÂ(I) and a chiral diene ligand.
This methodology offers access to diarylmethylamines in good yields
with excellent chiral purity at room temperature using MeOH as a solvent
and NEt<sub>3</sub> as a base. Its synthetic utility was demonstrated
by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
(<b>14</b>), an antagonist of the <i>N</i>-methyl-d-aspartate (NMDA) receptor
Enantioselective and Rapid Rh-Catalyzed Arylation of <i>N</i>‑Tosyl- and <i>N</i>‑Nosylaldimines in Methanol
Enantiomerically
enriched tosyl-protected diarylmethylamines were
rapidly prepared by the asymmetric addition of arylboronic acids to <i>N</i>-tosylaldimines under mild conditions in the presence of
a catalyst prepared in situ from RhÂ(I) and a chiral diene ligand.
This methodology offers access to diarylmethylamines in good yields
with excellent chiral purity at room temperature using MeOH as a solvent
and NEt<sub>3</sub> as a base. Its synthetic utility was demonstrated
by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
(<b>14</b>), an antagonist of the <i>N</i>-methyl-d-aspartate (NMDA) receptor
A Stereoselective Process for the Manufacture of a 2′-Deoxy-β‑d‑Ribonucleoside Using the Vorbrüggen Glycosylation
A practical
and scalable process for the manufacture of cladribine
(<b>1</b>) is described. Vorbrüggen glycosylation of
doubly silylated 2-chloroadenine <b>2</b> with protected 1-<i>O</i>-acetyl-2-deoxy-α,β-d-ribofuranose <b>3</b> under reversible conditions in the presence of 20 mol %
triflic acid in a solvent that selectively precipitated the desired
β-anomer β-<b>4a</b> whilst leaving the unwanted
α-anomer α-<b>4a</b> in solution to isomerise allowed
good overall stereoselectivity with exclusive regioselectivity. An
aging step allowed anomerisation of α-<b>4a</b> to β-<b>4a</b>, thereby improving the isolable yield of the β-anomer.
Direct filtration of the product mixture without a catalyst quench
or aqueous workup furnished the crude β-anomer β-<b>4a</b> in good yield (up to 68%) and purity (>95% by HPLC)
with
no regioisomers detected and only ∼1–3% (by HPLC) of
the undesired α-anomer. Deprotection of the crude, unpurified
intermediate β-<b>4a</b> followed by recrystallisation
provided drug-grade cladribine (<b>1</b>). The process includes
three isolation steps and was demonstrated on kilogram scales using
cGMP providing 99.8–99.9% pure cladribine in up to an overall
43% yield based on 2-chloroadenine (<b>5</b>). In contrast to
previous methods, column chromatography and/or bulky directing groups
were not required in the glycosylation step, a high pressure vessel
was not needed in the deprotection step, and only one dedicated recrystallisation
step was necessary
The Manufacture of a Homochiral 4‑Silyloxycyclopentenone Intermediate for the Synthesis of Prostaglandin Analogues
A process is described for the synthesis of kilogram
quantities
of homochiral 4-silyloxycyclopentenone (<i>R</i>)-<b>1</b>, a key intermediate useful for the synthesis of a plurality
of prostaglandin analogue drugs. Cyclopentenone (<i>R</i>)-<b>1</b> was synthesized in 14 isolated steps from furfural.
Key steps in the synthesis include a Wittig reaction, Piancatelli
rearrangement, and an enzymatic resolution featuring in situ recycling
of the undesired enantiomer furnishing the desired homochiral alcohol
in ≥99.5% ee. As a retort to the unsatisfactory coformation
of about 8% at best of the <i>trans</i>-olefin in the Wittig
reaction, a change to the order of several steps and the identification
of a recrystallisable, amine salt derivative, <b>2</b>, allowed
the unwanted isomer to be controlled to as low as 0.2%